This proposal describes a Specialized Center for Research (SCOR) in Ischemic Heart Disease that tests the hypothesis that the genetics, expression and function of cardiovascular estrogen receptors (ER) and estrogen-regulated target genes mediate protection against ischemic diseases and their sequelae, including vascular dysfunction, post- myocardial infarction remodeling, and arrhythmias. The program is based on widely noted gender differences in ischemic disease, beneficial effects of estrogen on cardiovascular diseases in women, and recent data demonstrating: 1) the presence of functional ER in cardiovascular diseases in women and men; 2) important ER target genes in cardiovascular tissues; and 3) an important role for ER and the genes they regulate in vascular and myocardial physiology. The hypothesis is investigated through genetic, molecular, cellular, animal and human studies in five highly integrated and cooperative projects that expand on existing strengths at New England Medical Center and Tufts University, as well as MIT, Boston University, and the Framingham, Heart Study. The five projects Proposed include: Project 1: "Genetics of Estrogen and Cardiovascular Responses", a genetic analysis of cardiovascular phenotypes and ER/ER-related genes from subjects in the Framingham Offspring study; Project 2: "Selective ER Modulation: Effects in Post Menopausal Women Following Myocardial Infarction", a secondary prevention trial at New England Medical Center with the selective ER modulator raloxifene; Project 3: "Cardiac ER and MI: Mouse Models", studies of ventricular remodeling, arrhythmogenic changes, and myocardial gene expression in wild-type, ERalphaKO and ERbetaKO ventricular remodeling, arrhythmogenic changes, and myocardial gene expression in wild-type, ERalphaKO and ERbetaKO mice following MI; Project 4: "ER Regulation of NO Synthases," studies of the rapid activation of endothelial eNOS by ERalpha, and the longer-term induction of vascular smooth muscle iNOS gene expression by ERbeta; and Project 5: "ER and Smooth Muscle BKCa Channels", studies of ER regulation of ion channel function ins ingle vascular smooth muscle cells. These Projects are served by three Cores: Administrative, Mouse (with Transgenic, Physiology, Cell Culture and Histology components), and Statistical, all build on existing Cores at the Molecular Cardiology Research Institute and Tufts-NEMC. Together, these five Projects define a broad-based program to explore new mechanisms of coronary myocardial regulation by ER with direct consequences for the diagnosis and management of ischemic cardiovascular diseases, and the potential to evolve a new class of therapies for these disorders.